Growth hormone secretagogues

ABSTRACT

The invention relates to compounds of formula I  
                 
 
     which are useful for elevating the plasma level of growth hormone in a mammal as well as for the treatment of growth hormone secretion deficiency, growth retardation in child and metabolic disorders associated with growth hormone secretion deficiency.

FIELD OF THE INVENTION

[0001] The invention relates to compounds, which are useful foradministration to a mammal thereby elevating the plasma level of growthhormone.

BACKGROUND OF THE INVENTION

[0002] (a) Description of Prior Art

[0003] Growth hormone (GH) or somatotropin, secreted by the pituitarygland constitute a family of hormones which biological activity isfundamental for the linear growth of a young organism but also for themaintenance of the integrity at its adult state. GH acts directly orindirectly on the peripheral organs by stimulating the synthesis ofgrowth factors (insulin-like growth factor-I or IGF-I) or of theirreceptors (epidermal growth factor or EGF). The direct action of GH isof the type referred to as anti-insulinic, which favors the lipolysis atthe level of adipose tissues. Through its action on IGF-I (somatomedinC) synthesis and secretion, GH stimulates the growth of the cartilageand the bones (structural growth), the protein synthesis and thecellular proliferation in multiple peripheral organs, including musclesand the skin. Through its biological activity, GH participates withinadults at the maintenance of a protein anabolism state, and plays aprimary role in the tissue regeneration phenomenon after a trauma.

[0004] The decrease of GH secretion with the age, demonstrated in humansand animals, favors a metabolic shift towards catabolism which initiatesor participates to the ageing of an organism. The loss in muscle mass,the accumulation of adipose tissues, the bone demineralization, the lossof tissue regeneration capacity after an injury, which are observed inelderly, correlate with the decrease in the secretion of GH.

[0005] GH is thus a physiological anabolic agent absolutely necessaryfor the linear growth of children and which controls the proteinmetabolism in adults.

[0006] Growth hormone (GH) secretion is regulated by two hypothalamicpeptides: GH-releasing hormone (GHRH), which exerts stimulatory effecton GH release and somatostatin which exhibits an inhibitory influence.In the last few years, several investigators have demonstrated that GHsecretion can also be stimulated by synthetic oligopeptides termedGH-releasing peptides (GHRP) such as hexarelin and various hexarelinanalogs (Ghigo et al., European Journal of Endocrinology, 136, 445-460,1997). These compounds act through a mechanism which is distinct fromthat of GHRH (C. Y. Bowers, in “Xenobiotic Growth HormoneSecretagogues”, Eds. B. Bercu and R. F. Walker, Pg. 9-28,Springer-Verlag, New York 1996) and by interaction with specificreceptors localized in the hypothalamus and pituitary gland ((a) G.Muccioli et al., Journal of Endocrinology, 157, 99-106, 1998; (b) G.Muccioli, “Tissue Distribution of GHRP Receptors in Humans”, AbstractsIV European Congress of Endocrinology, Sevilla, Spain, 1998). Recentlyit was demonstrated that GHRP receptors are present not only in thehypothalamo-pituitary system but even in various human tissues notgenerally associated with GH release (G. Muccioli et al., see above(a)).

[0007] GHRPs and their antagonists are described, for example, in thefollowing publications: C. Y. Bowers, supra, R. Deghenghi, “GrowthHormone Releasing Peptides”, ibidem, 1996, pg. 85-102; R. Deghenghi etal., “Small Peptides as Potent Releasers of Growth Hormone”, J. Ped.End. Metab., 8, pg. 311-313, 1996; R. Deghenghi, “The Development ofImpervious Peptides as Growth Hormone Secretagogues”, Acta Paediatr.Suppl., 423, pg. 85-87, 1997; K. Veeraraganavan et al., “Growth HormoneReleasing Peptides (GHRP) Binding to Porcine Anterior Pituitary andHypothalamic Membranes”, Life Sci., 50, Pg. 1149-1155, 1992; and T. C.Somers et al., “Low Molecular Weight Peptidomimetic Growth HormoneSecretagogues, WO 96/15148 (May 23, 1996).

[0008] The human GH has been produced by genetic engineering for aboutten years. Until recently most of the uses of GH were concerned withgrowth delay in children and now the uses of GH in adults are studied.The pharmacological uses of GH, GHRPs and growth hormone secretagoguesand may be classified in the following three major categories.

[0009] (b) Children Growth

[0010] Treatments with recombinant human growth hormone have been shownto stimulate growth in children with pituitary dwarfism, renalinsufficiencies, Tumer's syndrome and short stature. Recombinant humanGH is presently commercialized in Europe and in the United States forchildren's growth retardation caused by a GH deficiency and forchildren's renal insufficiencies. The other uses are under clinicaltrial investigation.

[0011] (c) Long Term Treatment for Adults and Elderly Patients

[0012] A decrease in GH secretion causes changes in body compositionduring aging. Preliminary studies of one-year treatment with recombinanthuman GH reported an increase in the muscle mass and in the thickness ofskin, a decrease in fat mass with a slight increase in bone density in apopulation of aged patients. With respect to osteoporosis, recentstudies suggest that recombinant human GH does not increase bonemineralization but it is suggested that it may prevent bonedemineralization in post-menopausal women. Further studies are currentlyunderway to demonstrate this theory.

[0013] (d) Short Term Treatment in Adults and Elderly Patients

[0014] In preclinical and clinical studies, growth hormone has beenshown to stimulate protein anabolism and healing in cases of burn, AIDSand cancer, in wound and bone healing.

[0015] GH, GHRPs and growth hormone secretagogues are also intended forveterinary pharmacological uses. GH, GHRPs and growth hormonesecretagogues stimulate growth in pigs during its fattening period byfavoring the deposition of muscle tissues instead of adipose tissues andincrease milk production in cows, and this without any undesired sideeffects which would endanger the health of the animals and without anyresidue in the meat or milk being produced. The bovine somatotropin(BST) is presently commercialized in the United States.

[0016] Most of the clinical studies presently undertaken were conductedwith recombinant GH. The GHRPs and growth hormone secretagogues areconsidered as a second generation product destined to replace in thenear future the uses of GH in most instances. Accordingly, the use ofGHRPs and growth hormone secretagogues present a number of advantagesover the use of GH per se.

[0017] Therefore, there is a need for compounds which, when administeredto a mammal, act as growth hormone secretagogues.

SUMMARY OF THE INVENTION

[0018] The present invention relates to new compounds which act asgrowth hormone secretagogues and, in general, to a method for elevatingthe plasma level of growth hormone in a mammal by administering theretoone or more of the compounds according to the invention. The inventionalso relates to methods for the treatment of growth hormone secretiondeficiency, for promoting wound healing, recovery from surgery orrecovery from debilitating illnesses, by administering to a mammal oneof these compounds in a therapeutically effective amount.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] In this description, the following abbreviations are used: D isthe dextro enantiomer, GH is growth hormone, Boc istert-butyloxycarbonyl, Z is benzyloxycarbonyl, N-Me is N-methyl, Pip is4-amino-piperidine-4-carboxylate, Inip is isonipecotyl, i.e.piperidine-4-carboxylate, Aib is a-amino isobutyryl, Nal isβ-naphthylalanine, Mrp is 2-Methyl-Trp, and Ala, Lys, Phe, Trp, His,Thr, Cys, Tyr, Leu, Gly, Ser, Pro, Glu, Arg, Val and Gln are the aminoacids alanine, lysine, phenylalanine, tryptophan, histidine, threonine,cysteine, tyrosine, leucine, glycine, serine, proline, glutamic acid,arginine, valine and glutamine, respectively. Furthermore gTrp is agroup of the formula

[0020] and gMrp a group of the formula

[0021] wherein * means a carbon atom which, when a chiral carbon atom,has a R or S configuration. The compounds of the invention are of thegeneral formula I:

[0022] wherein * means a carbon atom which, when a chiral carbon atom,has a R or S configuration, one of R¹ and R³ is an hydrogen atom and theother is a group of formula II

[0023] R² is a hydrogen atom, a linear or branched C₁-C₆ alkyl group, anaryl group, a heterocyclic group, a cycloalkyl group, a (CH₂)_(n)-arylgroup, a (CH₂)_(n)-heterocyclic group, a (CH₂)_(n)-cycloalkyl group, amethylsulfonyl group, a phenylsulfonyl group, a C(O)R⁸ group or a groupaccording to one or formulas III to VIII below:

[0024] R⁴ is a hydrogen atom or a linear or branched C₁-C₄-alkyl group,R⁵ is a hydrogen atom, a linear or branched C₁-C₄ alkyl group, a(CH₂)_(n)-aryl group, a (CH₂)_(n)-heterocycle group, a(CH₂)_(n)-cycloalkyl group or an amino group, R⁶ and R⁷ areindependently from each other a hydrogen atom or a linear or branchedC₁-C₄-alkyl group, R⁸ is a linear or branched C₁-C₆-alkyl group, R⁹,R¹⁰, R¹¹, R¹² , R¹³ , R¹⁴ , R¹⁵, and R¹⁶ are independently from eachother a hydrogen atom or a linear or branched C₁-C₄-alkyl group, m is 0,1 or 2 and n is 1 or 2.

[0025] A preferred embodiment of the invention are compounds wherein R²is hydrogen, R³ is a group of formula II and m is 0. Particularlypreferred are compounds, wherein linear or branched C₁-C₄ alkyl ismethyl, linear or branched C₁-C₆ alkyl is methyl, ethyl or i-butyl, arylis phenyl or naphthyl, cycloalkyl is cyclohexyl and the heterocyclicgroup is a 4-piperidinyl or 3-pyrrolyl group.

[0026] Specifically preferred compounds of the invention include thefollowing:

[0027] H-Aib-D-Trp-D-gTrp-CHO:

[0028] N-Me-Aib-D-Trp-D-gTrp-C(O)CH₃:

[0029] N-Me-Aib-D-Trp-N-Me-D-gTrp-C(O)CH₃:

[0030] In accordance with the present invention, it has been found thatthe compounds of the invention are useful for elevating the plasma levelof growth hormone in a mammal. Furthermore the compounds of the presentinvention are useful for the treatment of growth hormone secretiondeficiency, growth retardation in child and metabolic disordersassociated with growth hormone secretion deficiency, in particular inaged subjects.

[0031] Pharmaceutically acceptable salts of these compounds can be alsoused, if desired. Such salts include organic or inorganic additionsalts, such as hydrochloride, hydrobromide, phosphate, sulfate, acetate,succinate, ascorbate, tartrate, gluconate, benzoate, malate, fumarate,stearate or pamoate salts.

[0032] Pharmaceutical compositions of the invention are useful forelevating the plasma level of growth hormone in a mammal, including ahuman, as well for the treatment of growth hormone secretion deficiency,growth retardation in child and metabolic disorders associated withgrowth hormone secretion deficiency, in particular in aged subjects.Such pharmaceutical compositions can comprise a compound according tothe present invention or a pharmaceutically acceptable salt thereof, orcombinations of compounds according to the present invention orpharmaceutically acceptable salts thereof, optionally in admixture witha carrier, excipient, vehicle, diluent, matrix, or delayed releasecoating. Examples of such carriers, excipients, vehicles, and diluents,can be found in Remington's Pharmaceutical Sciences, 18th Edition, A. R.Gennaro, Ed., Mack Publishing Company, Easton, Pa, 1990.

[0033] The pharmaceutical compositions of the invention can comprise anadditional growth hormone secretagogue. Examples for suitable additionalgrowth hormone secretagogues are Ghrelin (cf. M. Kojima et al., Nature,402 (1999), 656-660), GHRP-1, GHRP-2 and GHRP-6.

[0034] Ghrelin:Gly-Ser-Ser(O-n-octanoyl)-Phe-Leu-Ser-Pro-Glu-His-Gln-Arg-Val-Gln-Gln-Arg-Lys-Glu-Ser-Lys-Lys-Pro-Pro-Ala-Lys-Leu-Gln-Pro-Arg

[0035] GHRP-1: Ala-His-D-B-Nal-Ala-Trp-D-Phe-Lys-NH₂

[0036] GHRP-2: D-Ala-D-B-Nal-Ala-Trp-D-Phe-Lys-NH₂

[0037] GHRP-6: His-D-Trp-Ala-Trp-D-Phe-Lys-NH₂

[0038] Any of the compounds according to the present invention can beformulated by the skilled in the art to provide medicaments which aresuitable for parenteral, buccal, rectal, vaginal, transdermal, pulmonaryor oral routes of administration.

[0039] The type of formulation of the medicament containing the compoundcan be selected according to the desired rate of delivery. For example,if the compounds are to be rapidly delivered, the nasal or intravenousroute is preferred.

[0040] The medicaments can be administered to mammals, including humans,at a therapeutically effective dose which can be easily determined byone of skill in the art and which can vary according to the species,age, sex and weight of the treated patient or subject as well the routeof administration. The exact level can be easily determined empirically.

EXAMPLES

[0041] The following examples illustrate the efficacy of the mostpreferred compounds used in the treatment of this invention.

Example 1 H-Aib-D-Trp-D-gTrp-CHO

[0042] Total synthesis (percentages represent yields obtained in thesynthesis as described below):

Z-D-Trp-NH₂

[0043] Z-D-Trp-OH (8.9 g; 26 mmol; 1 eq.) was dissolved in DME (25 ml)and placed in an ice water bath to 0° C. NMM (3.5 ml; 1.2 eq.), IBCF(4.1 ml; 1.2 eq.) and ammonia solution 28% (8.9 ml; 5 eq.) were addedsuccessively. The mixture was diluted with water (100 ml), and theproduct Z-D-Trp-NH₂ precipitated. It was filtered and dried in vacuo toafford 8.58 g of a white solid.

[0044] Yield=98%. C₁₉H₁₉N₃O₃, 337 g.mol⁻¹. Rf=0.46{Chloroform/Methanol/Acetic Acid (180/10/5)}.

[0045]¹²H NMR (250 MHZ, DMSO-d⁶): δ 2.9 (dd, 1H, H_(β), J_(ββ′)=14.5 Hz;J_(βα)=9.8 Hz); 3.1 (dd, 1H, H_(β′), J_(β′β)=14.5 Hz; Jβ′α=4.3 Hz); 4.2(sextuplet, 1H, H_(α)); 4.95 (s, 2H, CH₂ (Z)); 6.9-7.4(m, 11H); 7.5 (s,1H, H²); 7.65 (d, 1H, J=7.7 Hz); 10.8 (s, 1H, N¹H).

[0046] Mass Spectrometry (Electrospray), m/z 338 [M+H]⁺, 360 [M+Na]⁺,675 [2M+H]⁺, 697 [2M+Na]⁺.

Boc-D-Trp-D-Trp-NH₂

[0047] Z-D-Trp-NH₂ (3 g; 8.9 mmol; 1 eq.) was dissolved in DMF (100 ml).HCl 36% (845 μl; 1.1 eq.), water (2 ml) and palladium on activatedcharcoal (95 mg, 0.1 eq.) were added to the stirred mixture. Thesolution was bubbled under hydrogen for 24 hr. When the reaction went tocompletion, the palladium was filtered on celite. The solvent wasremoved in vacuo to afford HCl, H-D-Trp-NH₂ as a colorless oil.

[0048] In 10 l of DMF, HCl, H-D-Trp-NH₂ (8.9 mmol; 1 eq.), Boc-D-Trp-OH(2.98 g; 9.8 mmol; 1.1 eq.), NMM (2.26 ml; 2.1 eq.) and BOP (4.33 g; 1.1eq.) were added successively. After 1 hr, the mixture was diluted withethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogencarbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), andsaturated aqueous sodium chloride (100 ml). The organic layer was driedover sodium sulfate, filtered and the solvent removed in vacuo to afford4.35 g of Boc-D-Trp-D-Trp-NH₂ as a white solid.

[0049] Yield=85%. C₂₇H₃₁N₅O₄, 489 g.mol⁻¹. Rf=0.48{Chloroform/Methanol/Acetic Acid (85/10/5)}.

[0050]¹H NMR (200 MHZ, DMSO-d⁶): δ 1.28 (s, 9H, Boc); 2.75-3.36 (m, 4H,2 (CH₂)_(β); 4.14 (m, 1H, CH₆₀ ); 4.52 (m, 1H, CH_(α′)); 6.83-7.84 (m,14H, 2 indoles (11H), NH₂, NH (urethane) and NH (amide)); 10.82 (d, 1H,J=2 Hz, N¹H); 10.85 (d, 1H, J=2 Hz, N¹H).

[0051] Mass Spectrometry (Electrospray), m/z 490 [M+H]⁺, 512 [M+Na]⁺,979 [2M+H]⁺.

Boc-D-(NiBoc)Trp-D-(NiBoc)Tr -NH₂

[0052] Boc-D-Trp-D-Trp-NH₂ (3 g; 6.13 mmol; 1 eq.) was dissolved inacetonitrile (25 ml). To this solution, di-tert-butyl-dicarbonate (3.4g; 2.5 eq.) and 4-dimethylaminopyridine (150 mg; 0.2 eq.) weresuccessively added. After 1 hr, the mixture was diluted with ethylacetate (100 ml) and washed with saturated aqueous sodium hydrogencarbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), andsaturated aqueous sodium chloride (200 ml). The organic layer was driedover sodium sulfate, filtered and the solvent removed in vacuo. Theresidue was purified by flash chromatography on silica gel eluting withethyl acetate/hexane {5/5} to afford 2.53 g ofBoc-D-(N^(i)Boc)Trp-D-(N^(i)Boc)Trp-NH₂ as a white solid.

[0053] Yield=60%. C₃₇H₄₇N₅O₈, 689 g.mol⁻¹. Rf=0.23 {ethyl acetate/hexane(5/5)}.

[0054]¹H NMR (200 MHZ, DMSO-d⁶): δ 1.25 (s, 9H, Boc); 1.58 (s, 9H, Boc);1.61 (s, 9H, Boc); 2.75-3.4 (m, 4H, 2 (CH₂)_(β)); 4.2 (m, 1H, CH_(α′));4.6 (m, 1H, CH_(α)); 7.06-8 (m, 14 H, 2 indoles (10 H), NH (urethane),NH and NH₂ (amides)).

[0055] Mass Spectrometry (Electrospray), m/z 690 [M+H]⁺, 712 [M+Na]⁺,1379 [2M+H]⁺, 1401 [2M+Na]⁺.

Boc-D-(N^(i)Boc)Trp-D-g(N^(i)Boc)Trp-H

[0056] Boc-D-(N^(i)Boc)Trp-D-(N^(i)Boc)Trp-NH2 (3 g; 4.3 mmol; 1 eq.)was dissolved in the mixture DMF/water (18 ml/7 ml). Then, pyridine (772μl; 2.2 eq.) and Bis(Trifluoroacetoxy)IodoBenzene (2.1 g; 1.1 eq.) wereadded. After 1 hr, the mixture was diluted with ethyl acetate (100 ml)and washed with saturated aqueous sodium hydrogen carbonate (200 ml),aqueous potassium hydrogen sulfate (200 ml, 1M), and aqueous saturatedsodium chloride (200 ml). The organic layer was dried over sodiumsulfate, filtered and the solvent removed in vacuo.Boc-D-(N^(i)Boc)Trp-D-g(N^(i)Boc)Trp-H was used immediately for the nextreaction of formylation.

[0057] Rf=0.14 {ethyl acetate/hexane (7/3)}. C₃₆H₄₇N₅O₇, 661 g.mol⁻¹.

[0058]¹H NMR (200 MHZ, DMSO-d⁶): δ 1.29 (s, 9H, Boc); 1.61 (s, 18H, 2Boc); 2.13 (s, 2H, NH₂ (amine)); 3.1-2.8 (m, 4H, 2 (CH₂)_(β)); 4.2 (m,1H, CH_(α′)); 4.85 (m, 1H, CH_(α)); 6.9-8 (m, 12H, 2 indoles (10H), NH(urethane), NH (amide)).

[0059] Mass Spectrometry (Electrospray), m/z 662 [M+H]⁺, 684 [M+Na]⁺.

Boc-D-(N^(i)Boc)Trp-D-G(N^(i)Boc)Trp-CHO

[0060] Boc-D-(N^(i)Boc)Trp-D-g(N^(i)Boc)Trp-H (4.3 mmol; 1 eq.) wasdissolved in DMF (20 ml). Then, N,N-diisopropylethylamine (815 μl; 1.1eq.) and 2,4,5-trichlorophenylformate (1.08 g; 1.1 eq.) were added.After 30 minutes, the mixture was diluted with ethyl acetate (100 ml)and washed with saturated aqueous sodium hydrogen carbonate (200 ml),aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueoussodium chloride (200 ml). The organic layer was dried over sodiumsulfate, filtered and the solvent removed in vacuo. The residue waspurified by flash chromatography on silica gel eluting with ethylacetate/hexane {5/5} to afford 2.07 g ofBoc-D-(N^(i)Boc)Trp-D-g(N^(i)Boc)Trp-CHO as a white solid.

[0061] Yield=70%. C₃₇H₄₇N₅O₈, 689 g.mol⁻¹. Rf=0.27 }ethyl acetate/hexane(5/5)}.

[0062]¹H NMR (200 MHZ, DMSO-d⁶): δ 1.28 (s, 9H, Boc); 1.6 (s, 9H, Boc);1.61 (s, 9H, Boc); 2.75-3.1 (m, 4H, 2 (CH₂)_(β)); 4.25 (m, 1H,(CH)α_(A&B)); 5.39 (m, 0.4H, (CH)α′_(B)); 5.72 (m, 0.6H, (CH)α′_(A));6.95-8.55 (m, 14H, 2 indoles (10H), NH (urethane), 2 NH (amides), CHO(formyl)).

[0063] Mass Spectrometry (Electrospray), m/z 690 [M+H]⁺, 712 [M+Na]⁺,1379 [2M+H]⁺.

Boc-Aib-D-Trp-D-gTrp-CHO

[0064] Boc-D-(N^(i)Boc)Trp-D-g(N^(i)Boc)Trp-CHO (1.98 g; 2.9 mmol; 1eq.) was dissolved in a mixture of trifluoroacetic acid (16 ml), anisole(2 ml) and thioanisole (2 ml) for 30 minutes at 0° C. The solvents wereremoved in vacuo, the residue was stirred with ether and theprecipitated TFA, H-D-Trp-D-gTrp-CHO was filtered.

[0065] TFA, H-D-Trp-D-gTrp-CHO (2.9 mmol; 1 eq.), Boc-Aib-OH (700 mg; 1eq.), NMM (2.4 ml; 4.2 eq.) and BOP (1.53 g; 1.2 eq.) were successivelyadded in 10 ml of DMF. After 1 hr, the mixture was diluted with ethylacetate (100 ml) and washed with saturated aqueous sodium hydrogencarbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), andsaturated aqueous sodium chloride (200 ml). The organic layer was driedover sodium sulfate, filtered and the solvent removed in vacuo. Theresidue was purified by flash chromatography on silica gel eluting withethyl acetate to afford 1.16 g of Boc-Aib-D-Trp-D-gTrp-CHO as a whitesolid.

[0066] Yield=70%. C₃₁H₃₈N₆O₅, 574 g.mol⁻¹. Rf=0.26{Chloroform/Methanol/Acetic Acid (180/10/5)}.

[0067]¹H NMR (200 MHZ, DMSO-d⁶): δ 1.21 (s, 6H, 2 CH₃(Aib)); 1.31 (s,9H, Boc); 2.98-3.12 (m, 4H, 2 (CH₂)_(β)); 4.47 (m, 1H, (CH)α_(A&B)); 5.2(m, 0.4H, (CH)α′_(B)); 5.7 (m, 0.6H, (CH)α′_(A)); 6.95-8.37 (m, 15H, 2indoles (10H), 3 NH (amides), 1 NH (urethane), CHO (formyl)); 10.89 (m,2H, 2 N¹H (indoles)).

[0068] Mass Spectrometry (Electrospray), m/z 575 [M+H]⁺, 597 [M+Na]⁺,1149 [2M+H]⁺, 1171 [2M+Na]⁺.

H-Aib-D-Trp-D-gTrp-CHO

[0069] Boc-Aib-D-Trp-D-gTrp-CHO (1 g; 1.7 mmol) was dissolved in amixture of trifluoroacetic acid (8 ml), anisole (1 ml) and thioanisole(1 ml) for 30 minutes at 0° C. The solvents were removed in vacuo, theresidue was stirred with ether and the precipitated TFA,H-Aib-D-Trp-D-gTrp-CHO was filtered.

[0070] The product TFA, H-Aib-D-Trp-D-gTrp-CHO was purified bypreparative HPLC (Waters, delta pak, C18, 40×100 mm, 5 μm, 100 A).

[0071] Yield=52%. C₂₆H₃₀N₆O₃, 474 g.mol⁻¹.

[0072]¹H NMR (400 MHZ, DMSO-d⁶)+¹H/¹H correlation: δ 1.21 (s, 3H, CH₃(Aib)); 1.43 (s, 3H, CH₃ (Aib)); 2.97 (m, 2H, (CH₂)_(β)); 3.1 (m, 2H,(CH₂)_(β)); 4.62 (m, 1H, (CH)α_(A&B)); 5.32 (q, 0.4H, (CH)α′_(B)); 5.71(q, 0.6H, (CH)α′_(A)); 7.3 (m, 4H, H₅ and H₆ (2 indoles)); 7.06-7.2 (4d,2H, H_(2A) et H_(2B) (2 indoles)); 7.3 (m, 2H, H₄ or H₇(2 indoles));7.6-7.8 (4d, 2H, H_(4A) H_(7A) et H_(7B)); 7.97 (s, 3H, NH₂ (Aib) andCHO (Formyl)); 8.2 (d, 0.4H, NH_(1B) (diamino)); 8.3 (m, 2H, NH_(A&B));8.5 (d, 0.6H, NH_(1A) (diamino)); 8.69 (d, 0.6H, NH_(2A) (diamino));8.96 (d, 0.4H, NH_(2B) (diamino)); 10.8 (s, 0.6H, N¹H_(1A) (indole));10.82 (s, 0.4H, N¹H_(1B) (indole)); 10.86 (s, 0.6H, N¹H₂A (indole));10.91 (s, 0,4H, N¹H_(2B) (indole)).

[0073] Mass Spectrometry (Electrospray), m/z 475 [M+H]⁺, 949 [2M+H]⁺.

[0074] Analogous synthesis were performed for the following compounds:

Example 2 H-Aib-D-Mrp-D-gMrp-CHO

[0075] C₂₈H₃₄N₆O₃, 502 g.mol⁻¹.

[0076]¹H NMR (400 MHZ, DMSO-d⁶)+¹H/¹H correlation: δ 1.19 (s, 2H,(CH₃)_(1A) (Aib)); 1.23 (s, 1H, (CH₃)_(1B) (Aib)); 1.41 (s, 2H,(CH₃)_(2A) (Aib)); 1.44 (s, 2H, (CH₃)_(2B)(Aib)); 2.33-2.35 (4s, 6H, 2CH₃ (indoles)); 2.93 (m, 2H, (CH₂)_(β)); 3.02 (m, 2H, CH₂)_(β)); 4.65(m, 0.6H, (CH)α_(A)); 4.71 (m, 0.4H, (CH)α_(B)); 5.2 (m, 0.4H,(CH)α′_(B)); 5.6 (m, 0.6H, (CH)α′_(A)); 6.95 (m, 4H, H₅ and H₆ (2indoles)); 7.19 (m, 2H, H₄ or H₇ (2 indoles)); 7.6 (m, 2H, H₄ or H₇ (2indoles)); 7.9 (s, 1H, CHO (Formyl)); 7.95 (s, 2H, NH₂ (Aib)); 8.05 (d,0.4H, NH_(1B) (diamino)); 8.3 (m,1H, NH_(A&B)); 8.35 (m, 0.6H, NH_(1A)(diamino)); 8.4 (d, 0.6H, NH_(2A) (diamino)); 8.75 (d, 0.4H, NH_(2B)(diamino)); 10.69 (s, 0.6H, N¹H_(1A) (indole)); 10.71 (s, 0.4H, N¹H_(1B)(indole)); 10.80 (s, 0.6H, N¹H_(2A) (indole)); 10.92 (s, 0.4H, N¹H_(2B)(indole)).

[0077] Mass Spectrometry (Electrospray), m/z 503.1 [M+H]⁺.

Example 3 N-Me-Aib-D-Trp-D-gTrp-CHO

[0078] Boc-N-Me-Aib-OH (327 mg; 1.5 mmol; 2.6 eq.) was dissolved inmethylene chloride (10 ml) and cooled to 0° C. Then,dicyclohexylcarbodiimide (156 mg; 0.75 mmol; 1.3 eq.) was added. Themixture, after filtration of DCU, was added to a solution containingTFA, H-D-Trp-D-gTrp-CHO (0.58 mmol; 1 eq.) and triethylamine (267μl; 3.3eq.) in methylene chloride (5 ml). The reaction mixture was slowlywarmed to room temperature and stopped after 24 hr. The mixture wasdiluted with ethyl acetate (25 ml) and washed with saturated aqueoussodium hydrogen carbonate (50 ml), aqueous potassium hydrogen sulfate(50 ml, 1M), and saturated aqueous sodium chloride (50 ml). The organiclayer was dried over sodium sulfate, filtered and the solvent removed invacuo. The residue was purified by flash chromatography on silica geleluting with ethyl acetate/methanol {9/1 } to afford 180 mg (53%) ofBoc-N-Me-Aib-D-Trp-D-gTrp-CHO as a white foam.

[0079] Boc-N-Me-Aib-D-Trp-D-gTrp-CHO (180 mg; 0.3 mmol) was dissolved ina mixture of trifluoroacetic acid (8 ml), anisole (1 ml) and thioanisole(1 ml) for 30 minutes at 0° C. The solvents were removed in vacuo, theresidue was stirred with ether and the precipitated TFA,N-Me-Aib-D-Trp-D-gTrp-CHO was filtered.

[0080] The product TFA, N-Me-Aib-D-Trp-D-gTrp-CHO (39 mg; 15%) waspurified by preparative HPLC (Waters, delta pak, C18, 40×100 mm, 5 μm,100 A).

[0081] C₂₇H₃₂N₆O₃, 488 g.mol⁻¹.

[0082]¹H RMN (200 MHZ, DMSO-d⁶): δ 1.19 (s, 3H, CH₃ (Aib)); 1.42 (s, 3H,CH₃ (Aib)); 2.26 (s, 3H, NCH₃); 3.12 (m, 4H, 2 (CH₂)_(β)); 4.66 (m, 1H,(CH)_(α)); 5.32 et 1H, (CH)_(α′)); 6.9-7.8 (m, 10H, 2 indoles); 8 (m,1H, CHO (formyl)); 8.2-9 (m, 4H, 3 NH (amides) et NH (amine)); 10.87 (m,2H, 2 N¹H (indoles)).

[0083] Mass Spectrometry (Electrospray), m/z 489.29 [M+H]⁺.

Example 4 H-Aib-D-Trp-D-gTrp-C(O)CH₃

[0084] Boc-D-(N^(i)Boc)Trp-D-g(N^(i)Boc)Trp-H (0.72 mmol; 1 eq.) wasdissolved in DMF (20 ml). Then, N,N-diisopropylethylamine (259 ml; 2.1eq.) and acetic anhydride (749 ml; 1.1 eq.) were added. After 1 hr, themixture was diluted with ethyl acetate (100 ml) and washed withsaturated aqueous sodium hydrogen carbonate (100 ml), aqueous potassiumhydrogen sulfate (100 ml, 1M), and saturated aqueous sodium chloride (50ml). The organic layer was dried over sodium sulfate, filtered and thesolvent removed in vacuo. The residue was purified by flashchromatography on silica gel eluting with ethyl acetatethexane to afford370 mg (73%) of Boc-D-(N^(i)Boc)Trp-D-g(N^(i)Boc)Trp-C(O)CH₃ as a whitesolid.

[0085] Boc-D-(N^(i)Boc)Trp-D-g(N^(i)Boc)Trp-C(O)CH₃ (350 mg; 0.5 mmol; 1eq.) was dissolved in a mixture of trifluoroacetic acid (8 ml), anisole(1 ml) and thioanisole (1 ml) for 30 minutes at 0° C. The solvents wereremoved in vacuo, the residue was stirred with ether and theprecipitated TFA, H-D-Trp-D-gTrp-C(O)CH₃ was filtered.

[0086] In 10 ml of DMF, TFA, H-D-Trp-D-gTrp-C(Q)CH₃ (0.5 mmol; 1 eq.),Boc-Aib-OH (121 mg; 0.59 mmol; 1.2 eq.), NMM (230 μl; 4.2 eq.) and BOP(265 mg; 1.2 eq.) were successively added. After 1 hr, the mixture wasdiluted with ethyl acetate (25 ml) and washed with saturated aqueoussodium hydrogen carbonate (50 ml), aqueous potassium hydrogen sulfate(50 ml, 1M), and saturated aqueous sodium chloride (50 ml). The organiclayer was dried over sodium sulfate, filtered and the solvent removed invacuo. The residue was purified by flash chromatography on silica geleluting with ethyl acetate to afford 249 mg (85%) ofBoc-Aib-D-Trp-D-gTrp-C(O)CH₃ as a white foam.

[0087] Boc-Aib-D-Trp-D-gTrp-C(O)CH₃ (249 mg; 0.42 mmol) was dissolved ina mixture of trifluoroacetic acid (8 ml), anisole (1 ml) and thioanisole(1 ml) for 30 minutes at 0° C. The solvents were removed in vacuo, theresidue was stirred with ether and the precipitated TFA,H-Aib-D-Trp-D-gTrp-C(O)CH₃ was filtered.

[0088] The product TFA, H-Aib-D-Trp-D-gTrp-C(O)CH₃ (80 mg; 23%) waspurified by preparative HPLC (Waters, delta pak, C18, 40×100 mm, 5 mm,100 A).

[0089] C₂₇H₃₂N₆O₃, 488 g.mol⁻¹.

[0090]¹H NMR (200 MHZ, DMSO-d⁶): δ 1.22 (s, 3H, CH₃ (Aib)); 1.44 (s, 3H,CH₃ (Aib)); 1.8 (s, 3H, C(O)CH₃); 3.06 (m, 4H, 2 (CH₂)_(β)); 4.6 (m, 1H,(CH)_(α)); 5.6 (m, 1H, (CH)_(α′)); 6.9-7.8 (m, 10H, 2 indoles); 7.99 (s,2H, NH₂ (Aib)); 8.2-8.6 (m, 3H, 3 NH (amides)); 10.83 (s, 2H, 2 N¹H(indoles)).

[0091] Mass Spectrometry (Electrospray), m/z 489.32 [M+H]⁺.

Example 5 N-Me-Aib-D-Trp-D-gTrp-C(O)CH₃

[0092] Boc-N-Me-Aib-OH (1.09 g; 5.04 mmol; 4 eq.) was dissolved inmethylene chloride (10 ml) and cooled to 0° C. Then,dicyclohexylcarbodiimide (520 mg; 2.52 mmol; 2 eq.) was added. Themixture, after filtration of DCU, was added to a solution containingTFA, H-D-Trp-D-gTrp-C(O)CH₃ (940 mg; 1.26 mmol; 1 eq.) and triethylamine(580 ml; 3.3 eq.) in methylene chloride (5 ml). The reaction mixture wasslowly warmed to room temperature and stopped after 24 h. The mixturewas diluted with ethyl acetate (50 ml) and washed with saturated aqueoussodium hydrogen carbonate (100 ml), aqueous potassium hydrogen sulfate(100 ml, 1M), and saturated aqueous sodium chloride (100 ml). Theorganic layer was dried over sodium sulfate, filtered and the solventremoved in vacuo. The residue was purified by flash chromatography onsilica gel eluting with ethyl acetate/methanol {9/1 } to afford 530 mg(70%) of Boc-N-Me-Aib-D-Trp-D-gTrp-C(O)CH₃ as a white foam.

[0093] Boc-N-Me-Aib-D-Trp-D-gTrp-C(O)CH₃ (530 mg; 0.88 mmol) wasdissolved in a mixture of trifluoroacetic acid (8 ml), anisole (1 ml)and thioanisole (1 ml) for 30 minutes at 0° C. The solvents were removedin vacuo, the residue was stirred with ether and the precipitated TFA,N-Me-Aib-D-Trp-D-gTrp-C(O)CH₃ was filtered.

[0094] The product TFA, N-Me-Aib-D-Trp-D-gTrp-C(O)CH₃ (220 mg; 30%) waspurified by preparative HPLC (Waters, delta pak, C18, 40×100 mm, 5 mm,100 A).

[0095] C₂₆H₃₄N₆O₃, 502 g.mol⁻¹.

[0096]¹H NMR (200 MHZ, DMSO-d⁶): δ 1.17 (s, 3H, CH₃ (Aib)); 1.4 (s, 3H,CH₃ (Aib)); 1.78 (s, 3H, C(O)CH₃); 2.23 (s, 3H, NCH₃); 3.15 (m, 4H, 2(CH₂)_(β)); 4.7 (m, 1H, (CH_(α)); 5.55 (m, 1H, (CH)_(α′)); 6.9-7.9 (m,10H, 2 indoles); 8.2-8.8 (s, 4H, NH (amine) et 3 NH (amides)); 10.8 (s,2H, 2 N¹H (indoles)).

[0097] Mass Spectrometry (Electrospray), m/z 503.19 [M+H]⁺.

Example 6 Pip-D-Trp-D-gTrp-CHO

[0098] In 5 ml of DMF, TFA, H-D-Trp-D-gTrp-CHO (230 mg; 0.31 mmol; 1eq.), Boc-(N⁴Boc)Pip-OH (130 mg; 0.38 mmol; 1.2 eq.), NMM (145 μl; 4.2eq.) and BOP (167 mg; 0.38 mmol; 1.2 eq.) were successively added. After15 minutes, the reaction was over. The mixture was diluted with ethylacetate (25 ml) and washed with saturated aqueous sodium hydrogencarbonate (50 ml), aqueous potassium hydrogen sulfate (50 ml, 1M), andsaturated aqueous sodium chloride (50 ml). The organic layer was driedover sodium sulfate, filtered and the solvent removed in vacuo to affordBoc-(N⁴Boc)Pip-D-Trp-D-gTrp-CHO as a foam.

[0099] Boc-(N⁴Boc)Pip-D-Trp-D-gTrp-CHO (0.31 mmol) was dissolved in amixture of trifluoroacetic acid (8 ml), anisole (1 ml) and thioanisole(1 ml) for 30 minutes at 0° C. The solvents were removed in vacuo, theresidue was stirred with ether and TFA, H-Pip-D-Trp-D-gTrp-CHO wasfiltered.

[0100] The product TFA, H-Pip-D-Trp-D-gTrp-CHO (127 mg; 42%) waspurified by preparative HPLC (Waters, delta pak, C18, 40×100 mm, 5 μm,100 A).

[0101] C₂₈H₃₃N₇O₃, 515 g.mol⁻¹.

[0102]¹H RMN (200 MHZ, DMSO-d⁶): δ 1.81 (m, 2H, CH₂ (Pip)); 2.3 (m, 2H,CH₂ (Pip)); 3.1 (m, 8H, 2 (CH₂)_(β) et 2 CH₂ (Pip)); 4.68 (m, 1H,(CH)_(α)); 5.3 et 5.73 (2 m, 1H, (CH)_(α′)); 6.9-7.7 (m, 10H, 2indoles); 7.98 (2s, 1H, CHO (formyl)); 8.2-9.2 (m, 6H, NH₂ et NH (Pip)et 3 NH (amides)); 10.9 (m, 2H, 2 N¹H (indoles)).

[0103] Mass Spectrometry (Electrospray), m/z 516.37 [M+H]⁺, 538.27[M+Na]⁺.

Example 7 Pip-D-Trp-D-gTrp-C(O)CH₃

[0104] In 5 ml of DMF, TFA, H-D-Trp-D-gTrp-C(O)CH₃ (218 mg, 0.29 mmol; 1eq.), Boc-(N⁴Boc)Pip-OH (121 mg; 0.35 mmol; 1.2 eq.), NMM (135 μl; 4.2eq.) and BOP (155 mg; 0.35 mmol; 1.2 eq.) were successively added. After15 minutes, the reaction was over. The mixture was diluted with ethylacetate (25 ml) and washed with saturated aqueous sodium hydrogencarbonate (50 ml), aqueous potassium hydrogen sulfate (50 ml, 1M), andsaturated aqueous sodium chloride (50 ml). The organic layer was driedover sodium sulfate, filtered and the solvent removed in vacuo to affordBoc-(N⁴Boc)Pip-D-Trp-D-gTrp-C(O)CH³ as a foam.

[0105] Boc-(N⁴Boc)Pip-D-Trp-D-gTrp-C(O)CH₃ (0.29 mmol) was dissolved ina mixture of trifluoroacetic acid (8 ml), anisole (1 ml) and thioanisole(1 ml) for 30 minutes at 0° C. The solvents were removed in vacuo, theresidue was stirred with ether and the precipitated TFA,H-Pip-D-Trp-D-gTrp-C(O)CH₃ was filtered.

[0106] The product TFA, H-Pip-D-Trp-D-gTrp-C(O)CH₃ (135 mg; 47%) waspurified by preparative HPLC (Waters, delta pak, C18, 40×100 mm, 5 μm,100 A).

[0107] C₂₉H₃₅N₇O₃, 529 g.mol⁻¹.

[0108]¹H RMN (200 MHZ, DMSO-d⁶): δ 1.79 (m, 2H, CH₂ (Pip)); 1.81 (s, 3H,C(O)CH₃); 2.3 (m, 2H, CH₂ (Pip)); 3.1 (m, 8H, 2 (CH₂)β et 2 CH₂ (Pip));4.7 (m, 1H, (CH)α); 5.6 (m, 1H, (CH)_(α′)); 6.9-7.8 (m, 10H, 2 indoles);8.2-9 (m, 6H, NH₂ et NH (Pip) et 3 NH (amides)); 10.85 (m, 2H, 2 N¹H(indoles)).

[0109] Mass Spectrometry (Electrospray), m/z 530.39 [M+H]⁺, 552.41[M+Na]⁺.

Example 8 Isonipecotyl-D-Trp-D-gTrp-CHO

[0110] In 5 ml of DMF, TFA, H-D-Trp-D-gTrp-CHO (250 mg, 4.1 mmol; 1eq.), Fmoc-Isonipecotic-OH (144 mg; 4.1 mmol; 1.2 eq.), NMM (158 μl; 4.2eq.) and BOP (181 mg; 4.1 mmol; 1.2 eq.) were successively added. After15 minutes, the reaction was over. The mixture was diluted with ethylacetate (25 ml) and washed with saturated aqueous sodium hydrogencarbonate (50 ml), aqueous potassium hydrogen sulfate (50 ml, 1M), andsaturated aqueous sodium chloride (50 ml). The organic layer was driedover sodium sulfate, filtered and the solvent removed in vacuo to affordFmoc-Isonipecotyl-D-Trp-D-gTrp-CHO as a foam.

[0111] Fmoc-Isonipecotyl-D-Trp-D-gTrp-CHO (4.1 mmol) was dissolved in amixture of DMF (8 ml) and piperidine (2 ml) and allowed to stand for 30minutes. The solvents were removed in vacuo, the residue was stirredwith ether and the precipitated Isonipecotyl-D-Trp-D-gTrp-CHO wasfiltered.

[0112] The product Isonipecotyl-D-Trp-D-gTrp-CHO (81 mg; 28%) waspurified by preparative HPLC (Waters, delta pak, C18, 40×100 mm, 5 μm,100 A).

[0113] C₂₈H₃₂N₆O₃, 500 g.mol⁻¹.

[0114]¹H RMN (200 MHZ, DMSO-d⁶): δ 1.65 (m, 4H, 2 CH₂ (Pip)); 2.4 (m,1H, CH (Pip)); 2.7-3.3 (m, 8H, 2 (CH₂)_(β) et 2 CH₂ (Pip)); 4.6 (m, 1H,(CH)_(α)); 5.3 et 5.7 (2 m, 1H, (CH)_(α′)); 6.9-7.7 (m, 10H, 2 indoles);7.97 (2s, 1H, CHO (formyl)); 8-8.8 (m, 4H, NH (Pip) et 3 NH (amides));10.9 (m, 2H, 2 N¹H (indoles)).

[0115] Mass Spectrometry (Electrospray), m/z 501.36 [M+H]⁺.

Example 9 Isonipecotyl-D-Trp-D-gTrp-C(O)CH₃

[0116] In 5 ml of DMF, TFA, H-D-Trp-D-gTrp-C(O)CH₃ (250 mg, 0.33 mmol; 1eq.), Fmoc-Isonipecotic-OH (141 mg; 0.4 mmol; 1.2 eq.), NMM (155 μl; 4.2eq.) and BOP (178 mg; 0.4 mmol; 1.2 eq.) were successively added. After15 minutes, the reaction was over. The mixture was diluted with ethylacetate (25 ml) and washed with saturated aqueous sodium hydrogencarbonate (50 ml), aqueous potassium hydrogen sulfate (50 ml, 1M), andsaturated aqueous sodium chloride (50 ml). The organic layer was driedover sodium sulfate, filtered and the solvent removed in vacuo to affordFmoc-Isonipecotyl-D-Trp-D-gTrp-C(O)CH₃ as a foam.

[0117] Fmoc-Isonipecotyl-D-Trp-D-gTrp-C(O)CH₃ (0.33 mmol) was dissolvedin a mixture of DMF (8 ml) and piperidine (2 ml) and allowed to standfor 30 minutes. The solvents were removed in vacuo, the residue wasstirred with ether and the precipitatedIsonipecotyl-D-Trp-D-gTrp-C(O)CH₃ was filtered.

[0118] The product Isonipecotyl-D-Trp-D-gTrp-C(O)CH3 (65 mg; 13%) waspurified by preparative HPLC (Waters, delta pak, C18, 40×100 mm, 5 μm,100 A).

[0119] C₂₉H₃₄N₆O₃, 514 g.mol⁻¹.

[0120]¹H RMN (200 MHZ, DMSO-d⁶): δ 1.66 (m, 4H, 2 CH₂ (Pip)); 1.79 (s,3H, C(O)CH₃); 2.7-3.3 (m, 8H, 2 (CH₂)_(β) et 2 CH₂ (Pip)); 4.54 (m, 1H,(CH)_(α)); 5.59 (1H, (CH)_(α′)); 6.9-7.7 (m, 10H, 2 indoles); 8-8.6 (m,4H, NH (Pip) et 3 NH (amides)); 10.82 (m, 2H, 2 N¹H (indoles)).

[0121] Mass Spectrometry (Electrospray), m/z 515.44 [M+H]⁺.

Examples 10-62

[0122] The following compounds were prepared in similar manners:

Example 10 H-Aib-D-Mrp-gMrp-CHO Example 11 H-Aib-Trp-gTrp-CHO Example 12H-Aib-Trp-D-gTrp-CHO Example 13 H-D-Trp-gTrp-CHO Example 14N-Me-D-Trp-gTrp-CHO Example 15 N-Methylsulfonyl-D-Trp-gTrp-CHO Example16 N-Phenylsulfonyl-D-Trp-gTrp-CHO Example 17N-(3-Methyl-butanoyl)-D-Trp-gTrp-CO—CH₃ Example 18N-(3-Methyl-butanoyl)-D-Trp-gTrp-CHO Example 19Aib-D-Trp-gTrp-CO—CH₂—CH₃ Example 20 Aib-D-Trp-gTrp-CO—CH₂—CH(CH₃)—CH₃Example 21 Aib-D-Trp-gTrp-CO—CH₂-phenyl Example 22Aib-D-Trp-gTrp-CO-piperidin-4-yl Example 23Aib-D-Trp-gTrp-CO—CH₂-pyrrol-3-yl Example 24Aib-D-Trp-gTrp-CO—CH₂—CH₂-cyclohexyl Example 25N-Me-Aib-D-Trp-gTrp-CO—CH₂—CH₃ Example 26N-Me-Aib-D-Tip-gTrp-CO—CH₂—CH(CH₃)—CH₃ Example 27N-Me-Aib-D-Trp-gTrp-CO—CH₂-phenyl Example 28N-Me-Aib-D-Trp-gTrp-CO—CH₂-pyrrol-3-yl Example 29N-Me-Aib-D-Trp-gTrp-CO—CH₂—CH₂-cyclohexyl Example 30 Aib-D-Trp-gTrp-CHOExample 31 N-(3-amino-3-methyl-butanoyl)-D-Trp-gTrp-CO—CH₃ Example 32N-Acetyl-D-Trp-gTrp-CHO Example 33 N-Acetyl-D-Trp-gTrp-CO—CH₃ Example 34N-Formyl-D-Trp-gTrp-CHO Example 35 N-Formyl-D-Trp-gTrp-CO—CH₃ Example 36N-(1,1-dimethyl-2-amino-2-keto-ethyl)-D-Trp-gTrp-CHO Example 37N-(2-amino-2-methyl-propyl)-D-Trp-gTrp-CHO Example 38N-(2-amino-2-methyl-propyl)-D-Trp-gTrp-CO—CH₃ Example 39N-Me-Aib-D-Trp-D-gTrp-Isonipecotyl Example 40N-Me-Aib-D-Trp-N-Me-D-gTrp-C(O)CH₃ Example 41H-Aib-D-Trp-N-Me-D-gTrp-C(O)CH₃ Example 42H-Aib-(D)-1-Nal-g-(D)-1-Nal-formyl

[0123] C₃₀H₃₂N₄O₃, 496 g.mol⁻.

[0124]¹H RMN (200 MHz, DMSO-d⁶): δ 1.14 and 1.4 (2 m, 6H, 2 CH₃(Aib));3.17-3.55 (m, 4H. 2 (CH₂)_(β)); 4.82 (m, 1H, CHα); 5.5 and 5.82 (2 m,1H, CHα); 7.36-7.64 (m, 8H); 7.83-8 (m, 7H); 8.25-9.45 (m, 5H).

[0125] Mass Spectrometry (FAB), m/z 497 [M+H]⁺.

[0126] Analytic HPLC (Delta Pak 5μ C18 100A, 1 ml/min,214 nm, eluent:H₂O/ACN 0.1% TFA, gradient 0 to 100% ACN in 50 min), tr=20.28 min, 99%.Freezedried Compound.

Example 43 H-Aib-(D)-2-Nal-g-(D)-2-Nal-formyl

[0127] C₃₀H₃₂N₄O₃, 496 g.mol⁻¹.

[0128]¹H RMN (200 MHz, DMSO-d⁶): δ 1.18 and 1.36 (2 m, 6H, 2 CH₃(Aib));2.84-3.3 (m, 4H, 2 (CH₂)_(β)); 4.7 (m, 1H, CHα); 5.45 and 5.73 (2 m, 1H,CHα); 7.47-7.51 (m, 6H); 7.76-8.06 (m, 11H); 8.36-9.11 (m, 3H).

[0129] Mass Spectrometry (FAB), m/z 497 [M+H]⁺.

[0130] Analytic HPLC (Delta Pak 5μ C18 100A, 1 ml/min, 214 nm, eluent:H₂O/ACN 0.1% TFA, gradient 0 to 100% ACN in 50 min), tr=20.26 mm, 95%.Freezedried Compound.

Example 44 H-Aib-(D)-1-Nal-g-(D)-Trp-formyl

[0131] C₂₈H₃₁N₅O₃, 485 g.mol⁻¹.

[0132]¹H RMN (200 MHz, DMSO-d⁶): δ 1.15 and 1.42 (2 m, 6H, 2 CH₃(Aib));3.11-3.3 and 3.54-3.7 (m, 4H, 2 (CH₂)_(β)); 4.81 (m, 1H, CH_(α)); 5.4and 5.74 (2 m, 1H, CH_(α′)); 7.06-7.2 (m, 3H); 7.34-7.65 (m, 6H);7.91-8.1 (m, 4H); 8.2-8.4 (m, 1H); 8.55-9.5 (m, 3H); 10.95 (m, 1H, N¹H).

[0133] Mass Spectrometry (FAB), m/z 486 [M+H]⁺. Analytic HPLC (Delta Pak5μ C18 100A, 1 ml/min, 214 nm, eluent: H₂O/ACN 0.1% TFA, gradient 0 to100% ACN in 50 min), tr=17.33 mm, 92%. Freezedried Compound.

Example 45 H-Aib-(D)-2-Nal-g-(D)-Trp-formyl

[0134] C₂₈H₃₁N₅O₃, 485 g.mol⁻¹.

[0135]¹H RMN (200 MHz, DMSO-d⁶): δ 1.19 and 1.45 (2 m, 6H, 2 CH₃(Aib));2.93-3.3 (m, 4H, 2 (CH₂)_(β)); 4.71 (m, 1H, CH_(α)); 5.35 and 5.7 (2 m,1H, CH_(α′)); 7.05-7.1 (m, 2H); 7,2-7.34 (m, 1H); 7.47-7.53 (m, 4H);7.64 (m, 1H); 7.78-8 (m, 8H); 8.48-9.37 (m, 2H); 10.88-11.04 (m,1H,N¹H).

[0136] Mass Spectrometry (FAB), m/z 486 [M+H]⁺.

[0137] Analytic HPLC (Delta Pak 5μ C18 100A, 1 ml/min, 214 nm, eluent:H₂O/ACN 0.1% TFA, gradient 0 to 100% ACN in 50 min), tr=17.30min, 95%.Freezedried Compound.

Example 46 H-Aib-(D)-Trp-g-(D)-1-Nal-formyl

[0138] C₂₈H₃₁N₅O₃, 485 g.mol⁻¹.

[0139]¹H RMN (200 MHz, DMSO-d⁶): δ 1.23 and 1.41 (2 m, 6H, 2 CH₃(Aib));2.92-3.15 (m, 2H, (CH₂)_(β)); 3.4-3.6 (m, 2H, (CH₂)_(β)); 4.63 (m, 1H,CH_(α′)); 5.44 and 5.79 (2 m, 1H, CH_(α′)); 6.99-7.15 (m, 3H); 7.33 (m,1H); 7.45-8.1 (m, 11H); 8.34-9.37 (m, 3H); 10.83 (m, 1H).

[0140] Mass Spectrometry (FAB), m/z 486 [M+H]⁺.

[0141] Analytic HPLC (Symmetry shield 3.5μ C18 100A, 1 ml/min, 214 nm,eluent: H₂O/ACN 0.1% TFA, gradient 0 to 60% ACN in 15 min then 60 to100% ACN in 3 min), tr=10.00 min, 99%. Freezedried Compound.

Example 47 H-Aib-D-Trp-g-D-2-Nal-formyl

[0142] C₂₈H₃₁N₅O₃, 485 g.mol⁻¹.

[0143]¹H RMN (200 MHz, DMSO-d⁶): δ 1.22 and 1.43 (2 m, 6H, 2 CH₃ (Aib));2.85-3.3 (m, 4H, 2 (CH₂)_(β)); 4.64 (m, 1H, CH_(α)); 5.37 and 5.72 (2 m,1H, CH_(α′)); 6.97-7.13 (m, 3H); 7.32 (m,1H); 7.44-7.54 (m, 3H); 7.66(d, 1H); 7.78 (m, 1H); 7.86-8.02 (m, 7H); 8.33-9.4 (m, 2H); 10.82 (m,1H, N¹H).

[0144] Mass Spectrometry (FAB), m/z 486 [M+H]⁺.

[0145] Analytic HPLC (Delta pak 5μ C18 100A, 1 ml/min, 214 nm, eluent:H₂O/ACN 0.1% TFA, gradient 0 to 100% ACN in 25 min), tr=9.00 min, 99%.Freezedried Compound.

Example 48 H-Aib-(D)-Trp-g-(D)-3-(R/S)Dht-formyl

[0146] C₂₆H₃₂N₆O₃, 476 g.mol⁻¹.

[0147]¹H RMN (400 MHz, DMSO-d⁶): δ 1.12 (s, 3H, CH₃(Aib)); 1.32 (s, 3H,CH₃(Aib)); 1.73 (m, 1H, CH₂); 2.01 (m, 1H, CH₂); 2.9 (m, 1H); 3.03 (m,1H); 3.13 (m, 2H); 3.54 (m, 1H); 4.47 (m, 1H, CH_(α)); 5.10 and 5.52 (2m, 1H, CH_(α′)); 6.71-8.83 (m, 16H, 5H (Trp), 4H (Dht), 3 NH (amides),NH and NH₂ (amines), formyl); 10.7 (m, 1H, N¹H).

[0148] Mass Spectrometry (Electrospray), m/z 477.46 [M+H]⁺ 499.42[M+Na]⁺; 953.51 [2M+H]⁺.

[0149] Analytic HPLC (Delta Pak 5μ C18 100A, 1 ml/min, 214 nm, eluent:H₂O/ACN 0.1% TFA, gradient 0 to 100% ACN in 50 min), tr=9.40 min, 98%.Freezedried Compound.

Example 49 H-Aib-(D)-3(R/S)Dht-g-(D)-Trp-formyl

[0150] C₂₆H₃₂N₆O₃, 476 g.mol⁻¹.

[0151] RMN ¹H(400 MHz, DMSO-d⁶): δ 1.58 (s, 3H, CH₃ (Aib)); 1.85 (m, 1H,CH₂); 2.2 (m, 1H, CH₂); 3;1 (d, 2H); 3.35 (m, 2H); 3.56 (m, 1H); 3.7 (m,1H); 4.5 (m, 1H, CH_(α)); 5.33 and 5.71 (2 m, 1H, CH_(α′)); 6.88-8.91(m, 16H, 5H (Trp), 4H (Dht), 3 NH (amides), NH and NH₂ (amines),formyl); 10.92 and 10.97 (2s, 1H, N¹H).

[0152] Mass Spectrometry (Electrospray), m/z 477.33 [M+I]⁺; 499.42[M+Na]⁺ 953.51 [2M+H]⁺.

[0153] Analytic HPLC (Delta Pak 5μ C18 100A, 1 ml/min, 214 nm, eluent:H₂O/ACN 0.1% TFA, gradient 0 to 100% ACN in 50 min), tr=10.35 mm, 98%.Freezedried Compound.

Example 50 N-Me-Aib-(D)-Trp-g-(D)-3(R/S)Dht-acetyl

[0154] C₂₈H₃₆N₆O₃, 504 g.mol⁻¹.

[0155]¹H RMN (400 MHz, DMSO-d⁶): δ 1.42 (s, 3H, CH₃ (Aib)); 1.63 (s, 3H,CH₃ (Aib)); 2.72 (m, 3H, acetyl); 2.4 (m, 2H, CH₂); 2.5 (m, 3H, NCH₃);3.2-3.5 (m, 4H); 3.85 (m, 1H); 4.85 (m, 1H, CH_(α)); 5.76 (m, 1H,CH_(α′)); 7.04-8.86 (m, 14H, 5H (Trp), 4H (Dht), 3 NH (amides), 2 NH(amines)); 11.02 (2s, 1H, N¹H).

[0156] Mass Spectrometry (Electrospray), m/z 505,31 [M+H]⁺; 527,70[M+Na]⁺.

[0157] Analytic HPLC (Delta Pak 5μ C18 100A, 1 ml/min, 214 nm, eluent:H₂O/ACN 0.1% TFA, gradient 0 to 100% ACN in 50 min), tr=10.20 min, 98%.Freezedried Compound.

Example 51 N-Me-Aib-(D)-3(RS)Dht-g-(D)-Trp-acetyl

[0158] C₂₈H₃₆N₆O₃, 504 g.mol⁻¹.

[0159]¹H RMN (400 MHz, DMSO-d⁶): δ 1.58 (s, 6H, 2 CH₃ (Aib)); 1.81 (m,3H, acetyl); 1.98 (m, 1H, CH₂); 2.24 (m, 1H, CH₂); 2.54 (m, 3H, NCH₃);3.08 (d, 2H); 3.31 (m, 2H); 3.4 (m, 1H); 3.59 (m, 1H); 3.71 (m, 1H);4.52 (m, 1H, CH_(α′)); 5.61 (m, 1H, CH_(α′)); 6.9-8.92 (m, 14H, 5H(Trp), 4H (Dht), 3 NH (amides), 2 NH (amines)); 10.88 (s, 1H, N¹H).

[0160] Mass Spectrometry (Electrospray), m/z 505.43 [M+H]⁺; 527.52[M+Na]⁺.

[0161] Analytic HPLC (Delta Pak 5μ C18100A, 1 ml/min, 214 nm, eluent:H₂O/ACN 0.1% TFA, gradient 0 to 100% ACN in 50 min), tr=11 min, 98%.Freezedried Compound.

Example 52 N(Me)₂-Aib-(D)-Trp-(D)-gTrp-formyl

[0162] C₂₈H₃₆N₆O₃, 502 g.mol⁻¹.

[0163]¹H RMN (400 MHz, DMSO-d⁶): δ 1.2 (s, 3H, CH₃ (Aib)); 1.39 (s, 3H,CH₃ (Aib)); 2.29 (m, 3H, NCH₃); 2.99-3.33 (m, 4H, 2 (CH₂)_(β)); 4.68 (m,1H, CH)_(α)); 5.3 and 5.69 (m, 1H, CH)_(α′)); 6.97-7.72 (m, 10H, 2indoles) ;7.97 (2s, 1H, formyl); 8.2-9.47 (m, 3H, 3 NH (amides)); 10.85(m, 2H, 2 NH (indoles)).

[0164] Mass Spectrometry (Electrospray), m/z 503.45 [M+H]⁺.

[0165] Analytic HPLC (Symmetry shield 3.5μ C18 100A, 1 ml/min, 214 nm,eluent: H₂O/ACN 0.1% TFA, gradient 0 to 100% ACN in 15 min), tr=6.63min, 99%. Freezedried Compound.

Example 53 N(Me)₂-Aib-D-Trp-D-gTrp-acetyl

[0166] C₂₉H₃₆N₆O₃, 516 g.mol⁻¹.

[0167]¹H RMN (200 MHz, DMSO-d⁶): δ 1.22 (s, 3H, CH₃ (Aib)); 1.4 (s, 3H,CH₃ (Aib)); 1.8 (s, 3H, acetyl); 2.28 (d, 3H, NCH₃); 2.96-3.22 (m, 4H, 2(CH₂)_(β)); 4.7 (m, 1H, CH_(α)); 5.60 (m, 1H, (CH)_(α′)); 6.98-7.75 (m,10H, 2 indoles); 8.2-9.47 (m, 3H, 3 NH (amides)); 10.84 (m, 2H, 2 NH(indoles)).

[0168] Mass Spectrometry (Electrospray), m/z 517.34 [M+H]⁺.

[0169] Analytic HPLC (Symmetry shield 3.5 μ C18 100A, 1 ml/min, 214 nm,eluent: H₂O/ACN 0.1% TFA, gradient 0 to 100% ACN in 15 min), tr=7.07 mm,99%. Freezedried Compound.

Example 54 H-Acc³-(D)-Trp-(D)-gTrp-formyl

[0170] C₂₆H₂₈N₆O₃, 472 g.mol⁻¹.

[0171]¹H RMN (400 MHz, DMSO-d⁶): δ 1.11 and 1.5 (2 m, 4H,2 CH₂(Acc³));2.91-3.12 (m, 4H, 2 (CH₂)_(β)); 4.6 (m, 1H, CH_(α)); 5.3 and 5.7 (2 m,1H, CH_(α′)); 6.97-7.17 (m, 6H, indoles); 7.32 (m, 2H, indoles);7.62-7.72 (m, 2H, indoles); 7.97 (2s, 1H, formyl); 8.27-8.92 (m, 5H, 3NH (amides) and NH₂ (amine)); 10.80-10.90 (4s, 2H, 2 N¹H).

[0172] Mass Spectrometry (Electrospray), m/z 473.22 [M+H]⁺; 495.15[M+Na]⁺ 945.47 [2M+H]⁺; 967.32 [2M+Na]⁺.

[0173] Analytic HPLC (Delta Pak 5μ C18 100A, 1 ml/min, 214 nm, eluent:H₂O/ACN 0.1% TFA, gradient 0 to 100% ACN in 50 min), tr=14.20 min, 98%.Freezedried Compound.

Example 55 H-Acc⁵-(D)-Trp-(D)-gTrp-formyl

[0174] C₂₆H₂₈N₆O₃, 472 g.mol⁻¹.

[0175]¹H RMN (400 MHz, DMSO-d⁶): δ 1.51 and 2.31 (m, 8H, 4 CH₂ (Acc⁵));2.97-3.18 (m, 4H, 2 (CH₂)_(β)); 4.64 (m, 1H, CH_(α)); 5.31 and 5.69 (2m, 1H, CH_(α′)); 6.96-7.34 (m, 8H, indoles); 7.62-7.74 (m, 2H, indoles);7.96 (m, 3H, formyl and NH₂ (amine)); 8.48-8.96 (m, 3H, 3 NH (amides);10.80-10.90 (4s, 2H, 2 N¹H).

[0176] Mass Spectrometry (Electrospray), m/z 501.31 [M+H]⁺; 523.42[M+Na]⁺; 101.37 [2M+H]⁺.

[0177] Analytic HPLC (Delta Pak 5μ C18 100A, 1 ml/min, 214 nm, eluent:H₂O/ACN 0.1% TFA, gradient 0 to 100% ACN in 50 min), tr=15.35 min, 98%.Freezedried Compound.

Example 56 H-Acc⁶-(D)-Trp-(D)-gTrp-formyl

[0178] C₂₆H₂₈N₆O₃, 472 g.mol⁻¹.

[0179]¹H RMN (400 MHz, DMSO-d⁶): δ 1.29-1.57 (m, 8H, 4 CH₂ (Acc⁶)); 1.89and 2.04 (2 m, 2H, CH₂(Acc⁶)); 2.95-3.17 (m, 4H, 2 (CH₂)_(β)); 4.61 (m,1H, CH_(α)); 5.3 and 5.68 (2 m, 1H, CH_(α′)); 6.95-7.21 (m, 6H,indoles); 7.32 (m, 2H, indoles); 7.6 (m, 2H, indoles); 7.74 (m, 2H,indoles); 7.96 (m, 3H, formyl and NH₂ (amine)); 8.18-8.67 (m, 5H, 3 NH(amides)); 10.77-10.89 (4s,2H, 2N¹H).

[0180] Mass Spectrometry (Electrospray), m/z 515.11 [M+H]⁺.

[0181] Analytic HPLC (Delta Pak 5μ C18 100A, 1 ml/min, 214 nm, eluent:H₂O/ACN 0.1% TFA, gradient 0 to 100% ACN in 50 min), tr=15.9 min, 97%.Freezedried Compound.

Example 57 H-Dpg-(D)-Trp-(D)-gTrp-formyl

[0182] C₂₆H₂₈N₆O₃, 530 g.mol⁻¹.

[0183]¹H RMN (400 MHz, DMSO-d⁶): δ 0 (m, 1H, Dpg); 0.40 (m, 3H, Dpg);0.70 (m, 4H, Dpg); 1.01-1.51 (m, 5H, Dpg); 1.76 (m, 1H, Dpg); 2.82-2.95(m, 4H, 2 (CH₂)_(β)); 4.59 (m, 1H, CH_(α)); 5.3 and 5.54 (2 m, 1H,CH_(α′)); 6.81-7.09 (m, 6H, indoles); 7.19 (m, 2H, indoles); 7.48 (m,1H, indoles); 7.6-7.68 (m, 5H, 1H (indoles), formyl and NH₂ (amine);7.83-8.82 (m,3H, 3 NH (amides)); 10.69 and 10.76 (2 m, 2H, 2N¹H).

[0184] Mass Spectrometry (Electrospray), m/z 531.24 [M+I]⁺.

[0185] Analytic HPLC (Delta Pak 5μ C18 100A, 1 ml/min, 214 nm, eluent:H₂O/ACN 0.1% TFA, gradient 0 to 100% ACN in 50 mm), tr=15.35 mm, 98%.Freezedried Compound.

Example 58 H-Aib-(D)-Trp-(D)-gTrp-C(O)NHCH₂CH₃

[0186] C₂₆H₂₅N₇O₃, 517 g.mol⁻¹.

[0187]¹H RMN (400 MHz, DMSO-d⁶): δ 0.94 (t, 3H, NHCH₂CH ₃); 1.01 (s, 3H,CH₃ (Aib)); 1.08 (s, 3H, CH₃ (Aib)); 1.8 (s1, 2H, NH₂); 2.95-3.15 (m,6H, 2 (CH₂)_(β) and NHCH₂CH₃); 4.43 (m, 1H, CH_(α)); 5.39 (m, 1H,CH_(α′)); 6.02 (m, 1H); 6.22 (m, 1H); 6.9-7.56 (m, 10H, indoles); 8 (m,1H); 8.31 (m, 1H); 10.77 and 10.79 (2s, 2H, 2N¹H).

[0188] Mass Spectrometry (Electrospray), m/z 518.4 [M+H]⁺; 540.3[M+Na]⁺.

[0189] Analytic HPLC (Symmetry shield 3.5μ C18 100A, 1 ml/min, 214 nm,eluent: H₂O/ACN 0.1% TFA, gradient 0 to 100% ACN in 15 min), tr=7.12min, 99%. Freezedried Compound.

Example 59 N-Me-Aib-(D)-Trp-(D)-gTrp-C(O)NHCH₂CH₃ Example 60H-Aib-(R)-Me-Trp-(D)-gTrp-formyl Example 61H-Aib-(D)-Trp-(R)-Me-gTrp-formyl Example 62H-Me-Aib-(D)-Trp-(R)-Me-gTrp-acetyl Example 63 Evaluation of the GrowthHormone Releasing Activity of New Growth Hormone Secretagogues in theInfant Rat

[0190] Animals

[0191] Male 10-day-old Sprague Dawley rats, about 25 g body weight wereused.

[0192] Pups were received on the fifth day after birth and were housedunder controlled conditions (22±2° C., 65% humidity and artificial lightfrom 06.00 to 20.00 h). A standard dry diet and water were available adlibitum to the dams.

[0193] Experimental procedure

[0194] One hour before the experiments, pups were separated from theirrespective dams and were divided randomly into groups of eight each.

[0195] Pups were acutely challenged subcutaneously with 100 μl ofsolvent (DMSO, final dilution 1:300 in physiological saline), hexarelin(Tyr-Ala-His-D-Mrp-Ala-Trp-D-Phe-Lys-NH₂, used as a reference drug), ornew compounds (300 μg/kg) and killed by decapitation 15 min later.

[0196] Trunk blood was collected and centrifuged immediately. Plasmasamples were stored at −20° C. until assayed for the determination ofplasma GH concentrations.

[0197] Growth hormone concentrations in plasma were measured by RIAusing materials provided by the National Institute of Diabetes,Digestive and Kidney Diseases (NIDDK) of the National Institute ofHealth U.S.A.

[0198] Values were expressed in terms of the NIDDK-rat-GH-RP-2 standard(potency 21 U/mg) as ng/ml of plasma.

[0199] The minimum detectable value of rat GH was about 1.0 ng/ml, andintraassay variability was about 6%.

[0200] The obtained results of several test series, wherein the in vivoactivity in the rat was determined, are listed in tables 1 to 10. TABLE1 Example Structure GH ng/ml  1 H-Aib-D-Trp-D-gTrp-CHO 158.8 ± 39.4  13H-Aib-D-Trp-gTrp-CHO  58 ± 6.3 SOLVENT 15.0 ± 8.0  HEXARELINTyr-Ala-His-D-Mrp-Ala-Trp-D-Phe-  202 ± 32.7 Lys-NH₂

[0201] TABLE 2 Example Structure GH ng/ml 3 N-Me-Aib-D-Trp-D-gTrp-CHO 86.6 ± 12.6 4 H-Aib-D-Trp-D-gTrp-C(O)CH₃ 104.7 ± 13.5 5N-Me-Aib-D-Trp-D-gTrp-C(O)CH₃ 175.5 ± 37.2 SOLVENT 20.7 ± 0.9 HEXARELINTyr-Ala-His-D-Mrp-Ala-Trp-D-Phe- 134.5 ± 27.2 Lys-NH₂

[0202] TABLE 3 Example Structure GH ng/ml  6 Pip-D-Trp-D-gTrp-CHO 109.7± 10.1  7 Pip-D-Trp-D-gTrp-C(O)CH₃ 53.1 ± 6.6  8Isonipecotyl-D-Trp-D-gTrp-CHO 94.2 ± 8.6  9Isonipecotyl-D-Trp-D-gTrp-C(O)CH₃  61.2 ± 10.8 19Aib-D-Trp-gTrp-CO-CH₂-CH₃  79.8 ± 22.4 20Aib-D-Trp-gTrp-CO-Piperidin-4-yl 153.6 ± 30.6 SOLVENT 22.3 ± 5  HEXARELIN Tyr-Ala-His-D-Mrp-Ala-Trp-D-Phe- 114.7 ± 8.4  Lys-NH₂

[0203] TABLE 4 Example Structure GH ng/ml 39 N-Me-Aib-D-Trp-D-gTrp- 97.1± 21.0 Isonipecotyl 40 N-Me-Aib-D-Trp-N-Me-D-gTrp- 188.2 ± 28.5  C(O)CH₃41 H-Aib-D-Trp-N-Me-D-gTrp- 75.4 ± 15.0 C(O)CH₃ SOLVENT 10.55 ± 2.65 HEXARELIN Tyr-Ala-His-D-Mrp-Ala-Trp-D-Phe- 114.5 ± 12.9  Lys-NH₂

[0204] TABLE 5 Example Structure GH ng/ml 42H-Aib-(D)-1-Nal-g-(D)-1-Nal-formyl 25.05 ± 06.00 43H-Aib-(D)-2-Nal-g-(D)-2-Nal-formyl 37.33 ± 19.74 44H-Aib-(D)-1-Nal-g-(D)-1-Trp-formyl 15.04 ± 03.30 45H-Aib-(D)-2-Nal-g-(D)-1-Trp-formyl 13.91 ± 03.87 46H-Aib-(D)-Trp-g-(D)-1-Nal-formyl  8.26 ± 01.09 47H-Aib-(D)-Trp-g-(D)-2-Nal-formyl  9.04 ± 04.03 SOLVENT  6.49 ± 01.18HEXARELIN 276.01 ± 23.5 

[0205] TABLE 6 Example Structure GH ng/ml 48H-Aib-(D)-Trp-g-3(R/S)Dht-formyl 17.49 ± 2.40 49H-Aib-(D)-3(R/S)Dht-(D)-Trp-formyl 24.35 ± 4.85 50N-Me-Aib-(D)-Trp-(D)-3(R/S)Dht-acetyl 11.17 ± 1.35 51H-Me-Aib-(D)-3(R/S)Dht-(D)-Trp-acetyl 19.38 ± 4.16 SOLVENT 14.65 ± 0.92HEXARELIN 91.61 ± 4.09

[0206] TABLE 7 Example Structure GH ng/ml 52N(Me)₂-Aib-(D)-Trp-(D)-gTrp- 121.43 ± 29    formyl 53N(Me)₂-Aib-(D)-Trp-(D)-gTrp-acetyl 26.80 ± 5.64  SOLVENT 7.89 ± 1.77HEXARELIN 172.5 ± 38.53

[0207] TABLE 8 Example Structure GH ng/ml 60H-Aib-(R)-Me-Trp-(D)-gTrp-formyl 21.02 ± 3.43 61H-Aib-(D)-Trp-(R)-Me-gTrp-formyl 152.28 ± 43.76 62H-Me-Aib-(D)-Trp-(R)-Me-gTrp-acetyl 171.78 ± 10.32 SOLVENT  7.89 ± 1.77HEXARELIN  172.5 ± 38.53

[0208] TABLE 9 Example Structure GH ng/ml 54H-Acc³-(D)-Trp-(D)-gTrp-formyl 7.89 ± 3.20 55H-Acc⁵-(D)-Trp-(D)-gTrp-formyl 11.46 ± 1.18  56H-Acc⁶-(D)-Trp-(D)-gTrp-formyl 8.49 ± 0.40 57H-Dpg-(D)-Trp-(D)-gTrp-formyl 18.38 ± 2.88  SOLVENT 17.32 ± 1.70 HEXARELIN 89.91 ± 3.04 

[0209] TABLE 10 Example Structure GH ng/ml 58 H-Aib-(D)-Trp-(D)-gTrp-376.48 ± 43.24  C(O)NHCH₂CH₃ 59 N-Me-Aib-(D)-Trp-(D)-gTrp- 179.53 ±24.65  C(O)NHCH₂CH₃ SOLVENT 7.89 ± 1.77 HEXARELIN 172.5 ± 38.53

[0210] Furthermore the time dependence of the oral activity in the dog(1 mg/kg; per os) was estimated for example 1 (H-Aib-D-Trp-D-gTrp-CHO).Well-trained beagles of either sex, >10 year, 10-15 kg by weight, wereused. Animals were fed normal dry food with water ad libitum and were ona 12 h-light/12 h-dark regimen with on at 7.00. The compound wasadministered orally to the dogs which had fasted since 16.00 of thepreceding day. Blood samples were taken 20 min before administration, atadministration and 15, 30, 60, 90, 120 and 180 min after administration.The results are given in table 11. TABLE 11 NAME OF THE DOG Example RAZFORREST MEAN 1 DAKOTA JORMA DEGAN LEE MARKUS TAYLOR VALUE SEM t (min)Concentration GH (ng/ml) −20   0.48 3.58 2.14 1.43 2.45 2.32 2.07 0.38 0 0.35 2.75 1.64 2.01 2.55 1.41 1.79 1.03 15 2.11 8.91 3.58 6.38 6.114.8 5.32 1.02 30 0.54 6.85 6.37 8.48 6.9 3.89 5.5 1.07 60 0.17 2.65 3.024.41 6.51 4.34 3.52 0.84 90 0.4 2.47 2.61 6.42 5.18 4.43 3.59 0.66 120 3.58 2.48 1.94 3.71 4.54 4.28 3.42 0.38 180  3.46 2.82 1.49 3.18 4.123.18 3.04 0.36 AUC 328.53 658.38 510.64 888.91 944.26 721.34 675.3594.47

[0211]

1 1 1 28 PRT rat MOD_RES (3)..(3) o-n-octanoyl 1 Gly Ser Ser Phe Leu SerPro Glu His Gln Arg Val Gln Gln Arg Lys 1 5 10 15 Glu Ser Lys Lys ProPro Ala Lys Leu Gln Pro Arg 20 25

What is claimed is:
 1. Compounds of the formula I

wherein * means a carbon atom which, when a chiral carbon atom, has a R or S configuration, one of R¹ and R³ is an hydrogen atom and the other is a group of formula II

R² is a hydrogen atom, a linear or branched C₁-C₆ alkyl group, an aryl group, a heterocyclic group, a cycloalkyl group, a (CH₂)_(n)-aryl group, a (CH₂)_(n)-heterocyclic group, a (CH₂),-cycloalkyl group, a methylsulfonyl group, a phenylsulfonyl group, a C(O)R⁸ group or a group according to one of formulas III to VIII:

R⁴ is a hydrogen atom or a linear or branched C₁-C₄ alkyl group, R⁵ is a hydrogen atom, a linear or branched C₁-C₄ alkyl group, a (CH₂)_(n)-aryl group, a (CH₂)_(n)-heterocyclic group, a (CH₂)_(n)-cycloalkyl group or an amino group, R₆ and R₇ are independently from each other a hydrogen atom or a linear or branched C₁-C₄-alkyl group, R₈ is a linear or branched C₁-C₆-alkyl group, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, and R₁₆ are independently from each other a hydrogen atom or a linear or branched C₁-C₄-alkyl group, m is 0, 1 or 2 and n is 1 or
 2. 2. Compounds according to claim 1, wherein R² is hydrogen, R³ is a group of formula II and m is
 0. 3. Compounds according to claim 2, wherein the linear or branched C₁-C₄ alkyl group is methyl, the linear or branched C₁-C₆ alkyl group is methyl, ethyl or i-butyl, aryl is phenyl or naphthyl, cycloalkyl is cyclohexyl and the heterocyclic group is a 4-piperidinyl or 3-pyrrolyl group.
 4. A compound which is


5. A compound which is


6. A pharmaceutical composition, comprising a therapeutically effective amount of the compound of claim
 1. 7. The composition of claim 6, in combination with a pharmaceutically acceptable carrier.
 8. The composition of claim 6, in combination with an additional growth hormone secretagogue.
 9. A method for elevating the plasma level of growth hormone in a mammal comprising administering to a mammal a therapeutically effective amount of a compound according to claim 1 so as to elevate the plasma level of growth hormone.
 10. A method for the treatment of growth hormone secretion deficiency comprising administering to a mammal a therapeutically effective amount of a compound according to claim 1 so as to treat the growth hormone secretion deficiency.
 11. A method for the treatment of growth retardation in a child comprising administering to a patient a therapeutically effective amount of a compound according to claim 1 so as to treat the growth retardation.
 12. A method for the treatment of metabolic disorders associated with growth hormone secretion deficiency comprising administering to a patient a therapeutically effective amount of a compound according to claim 1 so as to treat the metabolic disorder.
 13. The method of claim 12, wherein the patient is aged.
 14. A method for promoting wound healing, recovery from surgery or recovery from debilitating illnesses, which comprises administering a therapeutically effective amount of a compound according to claim 1 so as to promote the healing or recovery.
 15. The method of claim 14, wherein the method comprises promoting wound healing.
 16. The method of claim 14, wherein the method comprises promoting recovery from surgery.
 17. The method of claim 14, wherein the method comprises promoting recovery from one or more debilitating illnesses. 